Obesity is an increasing worldwide problem and is characterized by increased levels of leptin. High fat diets also increase serum leptin levels. This experiment will focus on two strains of rats: the Osborne-Mendel which becomes obese when eating a high fat diet and the S5B/P1 which does not. The OM rat has higher leptin levels than the S5B but upon ICV administration of leptin the response is the same in the two strains. Three mechanisms to explain why the OM rat is less sensitive to peripheral leptin will be tested. Aim 1: Impaired level of entry into the CNS. In this aim, leptin will be tested. Aim 1: Impaired level of entry into the CNS. In this aim, peripheral leptin will be administered and food intake measured. The CSF/serum leptin peripheral leptin will be administered and food intake measured. And lastly, the effect of peripheral leptin on hypothalamic leptin signaling pathways will be measured. Aim 2: Reduction in leptin response in the CNS. This aim will measure the effect of leptin on the NPY and POMC cascades and on the food intake response to peripheral injection on NPY. Aim 3: Decreasing SOCS-3 in the brain. This aim will measure the effect of adrenalectomy on peripherally administered leptin and the hypothalamic signaling pathway. These experiments will use molecular and behavioral approaches to examine the possibility that one or all of these mechanisms may provide insight into why obese individuals are leptin resistant.